Intra‐uterine insemination for unexplained subfertility

Susanne M Veltman‐Verhulst; Edward Hughes; Reuben Olugbenga Ayeleke; Ben J Cohlen

doi:10.1002/14651858.CD001838.pub5

Intra‐uterine insemination for unexplained subfertility

Appendices

Appendix 1. MDSG search strategy

01.01.15

Keywords CONTAINS "unexplained and endometriosis related infertility" or "unexplained infertility" or "unexplained subfertility" or Title CONTAINS "unexplained and endometriosis related infertility" or "unexplained infertility" or "unexplained subfertility"

AND

Keywords CONTAINS "Intrauterine Insemination" or "intrautero tuboperitoneal insemination" or "IUI" or "artifical insemination by donor" or "artifical insemination by partner" or "artificial insemination" or Title CONTAINS "Intrauterine Insemination" or "intrautero tuboperitoneal insemination" or "IUI" or "artifical insemination by donor" or "artifical insemination by partner" or "artificial insemination"

Appendix 2. CENTRAL search strategy

Database: EBM Reviews ‐ Cochrane Central Register of Controlled Trials <November 2015>

1 exp insemination, artificial/ or exp insemination, artificial, heterologous/ or exp insemination, artificial, homologous/ (296)
2 insemination.tw. (825)
3 iui.tw. (409)
4 or/1‐3 (919)
5 subfertil$.tw. (219)
6 infertil$.tw. (2489)
7 superovulation.tw. (142)
8 (unexplained adj2 sterility).tw. (3)
9 ovulation induction.tw. (557)
10 clomiphene.tw. (848)
11 exp Infertility/ (1670)
12 or/5‐11 (3906)
13 4 and 12 (557)

Appendix 3. MEDLINE search strategy

Database: Ovid MEDLINE(R) <1950 to December 2015>

1 exp insemination, artificial/ or exp insemination, artificial, heterologous/ or exp insemination, artificial, homologous/ (10482)
2 insemination.tw. (13177)
3 iui.tw. (1347)
4 or/1‐3 (17570)
5 subfertil$.tw. (4007)
6 infertil$.tw. (47182)
7 superovulation.tw. (1773)
8 (unexplained adj2 sterility).tw. (48)
9 ovulation induction.tw. (3103)
10 clomiphene.tw. (4578)
11 exp Infertility/ (56499)
12 randomized controlled trial.pt. (421692)
13 controlled clinical trial.pt. (92568)
14 randomized.ab. (343500)
15 placebo.tw. (176322)
16 clinical trials as topic.sh. (180817)
17 randomly.ab. (247477)
18 trial.ti. (151571)
19 cross over.ab. (18272)
20 or/12‐19 (1027804)
21 (animals not (humans and animals)).sh. (4077418)
22 20 not 21 (947417)
23 or/5‐11 (83460)
24 4 and 23 (4629)
25 24 and 22 (536)

Appendix 4. EMBASE search strategy

Database: Ovid EMBASE <1980 to December 2015>

1 exp artificial insemination/ (13129)
2 insemination.tw. (14203)
3 iui.tw. (2331)
4 or/1‐3 (20211)
5 exp ovulation induction/ (11436)
6 subfertil$.tw. (5054)
7 infertil$.tw. (62456)
8 superovulation.tw. (1943)
9 unexplained.tw. (36152)
10 ovulation induction.tw. (4192)
11 clomiphene.tw. (5175)
12 exp Infertility/ (98546)
13 or/5‐12 (156978)
14 4 and 13 (6953)
15 Clinical Trial/ (854455)
16 Randomized Controlled Trial/ (391145)
17 exp randomization/ (69171)
18 Single Blind Procedure/ (21435)
19 Double Blind Procedure/ (125380)
20 Crossover Procedure/ (45488)
21 Placebo/ (267953)
22 Randomi?ed controlled trial$.tw. (128448)
23 Rct.tw. (19108)
24 random allocation.tw. (1475)
25 randomly allocated.tw. (23799)
26 allocated randomly.tw. (2078)
27 (allocated adj2 random).tw. (745)
28 Single blind$.tw. (16729)
29 Double blind$.tw. (157482)
30 ((treble or triple) adj blind$).tw. (511)
31 placebo$.tw. (225354)
32 prospective study/ (317836)
33 or/15‐32 (1531254)
34 case study/ (35526)
35 case report.tw. (297077)
36 abstract report/ or letter/ (947549)
37 or/34‐36 (1273469)
38 33 not 37 (1490953)
39 38 and 14 (1138)

Appendix 5. PsycINFO search strategy

Database: PsycINFO <1806 to December Week 3 2015>

1 exp reproductive technology/ (1530)
2 insemination.tw. (629)
3 iui.tw. (27)
4 or/1‐3 (1912)
5 subfertil$.tw. (71)
6 infertil$.tw. (2818)
7 superovulation.tw. (3)
8 (unexplained adj2 sterility).tw. (1)
9 ovulation induction.tw. (19)
10 clomiphene.tw. (46)
11 or/5‐10 (2901)
12 4 and 11 (571)
13 random*.ti,ab,hw,id. (149863)
14 trial*.ti,ab,hw,id. (139796)
15 controlled stud*.ti,ab,hw,id. (10062)
16 placebo*.ti,ab,hw,id. (34029)
17 ((singl* or doubl* or trebl* or tripl*) and (blind* or mask*)).ti,ab,hw,id. (24142)
18 (cross over or crossover or factorial* or latin square).ti,ab,hw,id. (23991)
19 (assign* or allocat* or volunteer*).ti,ab,hw,id. (131093)
20 treatment effectiveness evaluation/ (19468)
21 mental health program evaluation/ (1947)
22 exp experimental design/ (50867)
23 "2000".md. (31997)
24 or/13‐23 (421988)
25 12 and 24 (21)

Appendix 6. Prognostic factors in included studies

Study ID	Age distribution	Subfertility years	Prim/Sec infertility	Previous treatment	Stimulation Method	Single insemination
1.	IUI versus Timed intercourse both in natural cycle	1 study
Bhattacharya 2008	TI+NC: 32 (±3.4) IUI+NC: 32 (±3.7) (TI is expectant management)	TI+NC: 30 (25 ‐ 38) IUI+NC:30 (25 ‐ 40) _{months (Inter quartile range)}	Mixed 117/386 (30%) Secondary	Not stated	No stimulation	Single
2.	IUI versus Timed intercourse both in stimulated cycle	7 studies
Agarwal 2004	IUI+OH: 29.52 (±3.65) TI +OH: 28,83 (±4,76)	IUI+OH: 4.91(±2.72) TI+OH: 4.93 (±3.27)	Mixed 32/113 (28%) secondary	No	CC 50‐150 mg	Single
Arcaini 1996	IUI+OH: 34.6 (±4.9) TI+OH: 33.4 (±4.7)	IUI+OH: 4.2 (±1.6) TI+OH: 3.9 (±2.3)	Mixed 7/68 (10%) secondary	Not stated	High dose: CC100mg and hMG 75‐225IU	Double
Chung 1995	IUI+OH: 31.8 (±3.1) TI+OH: 32.1 (±4.0)	IUI+OH: 4.7 (±2.0) TI+OH: 5.3 (±2.6)	Not clear	Not stated	hMG 150IU starting dose and GnRHa	IUI: Single TI: Double
Crosignani 1991	< 38 yrs	> 3 yrs	Not clear	Probably	Not stated	Not stated
Janko 1998	Not stated	> 3 yrs	Not clear	Not stated	hMG (10 amp per cycle)	Not stated
Karlstrom 1993	32 (range 21‐38)	5 (range 2‐14)	Mixed 49/148 (33%) secondary (incl Pt in DIPI groups)	No	hMG (low dose step up) 75 IU starting dose OR CC 100mg	IUI: Single TI: Double
Melis 1995	33.1 (±5.2)	4.3 (±1.4)	Not clear	Yes, all patients	High dose: FSH 225IU	Single
3.	IUI in natural cycle versus IUI in stimulated cycle
Arici 1994	33 (range 24‐41)	3.5 (range 1‐15)	Not clear	No	CC 50 mg	IUI+NC: Double IUI+OH: Single
Goverde 2000	IUI+NC: 31.6 (±3.7) IUI+OH: 31.7 (± 3.9)	IUI+NC: 3.9 (±1.7) IUI+OH: 4.2 (±1.9)	Mixed 13.5% secondary	Not stated	hMG 75IU starting dose	Single
Guzick 1999	IUI+NC: 32 (±4) IUI+OH: 32 (±4) <40 yrs	IUI+NC: 3.8 (±2.6) IUI+OH: 3.5 (±2.2)	Mixed 40% secondary	No	FSH 150IU	Single
Murdoch 1991	IUI+NC: 30.5 (±3.1) IUI+OH: 30.1 (±2.9)	IUI+NC: 5.7 (±2.4) IUI+OH: 5.1 (±1.9)	Mixed 5/34 (15%) secondary	No	hMG (low dose) 75IU + GnRHa	IUI+OH: Single IUI+NC: till USS evidence of ovulation
4.	IUI with OH versus TI in natural cycle	1 study
Deaton 1990	33 (±4.0)	3.5 (±1.7)	Mixed 21/51 (41%) secondary	Not stated	CC 50 mg	Single
Steures 2006	IUI+OH: 33 (±3.4) TI+NC: 33 (±3.1) (TI is expectant management)	IUI+OH: 2.0 (±0.5) TI+NC: 1.9 (±0.5)	Mixed 58/253 (23%) secondary	Not stated	FSH 37‐150 IU or CC 50‐150 mg	Not stated
5.	IUI in natural cycle versus TI with OH
Bhattacharya 2008	TI+OH: 32 (±3.5) IUI+NC: 32 (±3.7)	TI+OH: 30 (24 ‐ 38) IUI+NC: 30 (25 ‐ 40) _{months (Inter quartile range)}	Mixed 109/387 (28%)	Not stated	CC 25‐50 mg	Single
	* Mean age in years (± SD) or range	* Mean duration in years (± SD) or range			* Daily dose

Appendix 7. Sensitivity analyses: intra‐uterine insemination (IUI) versus timed intercourse (TI) both in a stimulated cycle

	Analysis	Number of studies	OR	95% CI	Heterogeneity (P)	I² (%)
LIVE BIRTH RATE	Main analysis (All cycles, by ITT, fixed effect, Agarwal 2004 excluded)	2	1.59	0.88 ‐ 2.88	0.06	72
	Not by ITT	2	1.46	0.80 ‐ 2.66	0.06	71
	Random effect	2	1.65	0.52 ‐ 5.23	0.06	72
	Agarwal 2004 included	3	0.81	0.51 ‐ 1.28	0.0002	88

PREGNANCY RATE	Main analysis (All cycles, by ITT, fixed effect, Agarwal 2004 excluded)	6	1.69	1.14 ‐ 2.53	0.37	8
	Not by ITT	6	1.65	1.10 ‐ 2.47	0.36	10
	Random effect	6	1.72	1.11‐ 2.65	0.37	8
	Agarwal 2004 included	7	1.25	0.88 ‐ 1.78	0.02	60
	Adequate methodology (Chung 1995, Melis 1995)	2	1.70	0.96 ‐ 3.02	0.06	71.7
	Previous treatment excluded (Melis 1995 excluded)	5	2.03	1.27 ‐ 3.26	0.50	0
	Calculated data excluded (Janko 1998 excluded)	5	1.71	1.11 ‐ 2.63	0.26	23
	Trials including pt with endometriosis excluded (Karlstrom 1993 excluded)	5	1.83	1.20 ‐ 2.79	0.38	4

Appendix 8. Sensitivity analyses: IUI in a natural cycle versus IUI in a stimulated cycle

	Analysis	Number of studies	OR	95% CI	Heterogeneity (p)	I² (%)
LIVE BIRTH RATE	Main analysis (All cycles, by ITT, fixed effect)	4	0.48	0.29 ‐ 0.82	0.55	0
	Not by ITT	4	0.47	0.28 ‐ 0.81	0.79	0
	Random effect	4	0.48	0.28 ‐ 0.85	0.55	0
	Cross over trials excluded (Arici 1994 excluded)	3	0.50	0.29 ‐ 0.85	0.39	0
	Adequate Methodology (Guzick 1999 excluded, Randomisation not per unexplained pt)	3	0.59	0.29 ‐ 1.21	0.47	0
	Endometriosis (Arici 1994, Guzick 1999 excl)	2	0.64	0.30 ‐ 1.34	0.29	9

Figure 1

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

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Figure 2

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

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Figure 3

Study flow diagram.

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Figure 4

Funnel plot of comparison: 2 IUI versus TI both in stimulated cycle, outcome: 2.3 Pregnancy rate per couple (all cycles).

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Analysis 1.1

Comparison 1 IUI versus TI or expectant management both in natural cycle, Outcome 1 Live birth rate per couple (all cycles).

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Analysis 1.2

Comparison 1 IUI versus TI or expectant management both in natural cycle, Outcome 2 Multiple pregnancy rate per couple.

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Analysis 1.3

Comparison 1 IUI versus TI or expectant management both in natural cycle, Outcome 3 Pregnancy rate per couple (all cycles).

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Analysis 1.4

Comparison 1 IUI versus TI or expectant management both in natural cycle, Outcome 4 Miscarriage rate per couple.

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Analysis 1.5

Comparison 1 IUI versus TI or expectant management both in natural cycle, Outcome 5 Ectopic pregnancy rate per couple.

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Analysis 2.1

Comparison 2 IUI versus TI or expectant management both in stimulated cycle, Outcome 1 Live birth rate per couple (all cycles).

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Analysis 2.2

Comparison 2 IUI versus TI or expectant management both in stimulated cycle, Outcome 2 Multiple pregnancy rate per couple.

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Analysis 2.3

Comparison 2 IUI versus TI or expectant management both in stimulated cycle, Outcome 3 Pregnancy rate per couple (all cycles).

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Analysis 2.4

Comparison 2 IUI versus TI or expectant management both in stimulated cycle, Outcome 4 Moderate or severe ovarian hyperstimulation syndrome rate per woman.

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Analysis 2.5

Comparison 2 IUI versus TI or expectant management both in stimulated cycle, Outcome 5 Miscarriage rate per couple.

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Analysis 2.6

Comparison 2 IUI versus TI or expectant management both in stimulated cycle, Outcome 6 Ectopic pregnancy rate per couple.

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Analysis 3.1

Comparison 3 IUI in natural cycle versus IUI in stimulated cycle, Outcome 1 Live birth rate per couple (all cycles).

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Analysis 3.2

Comparison 3 IUI in natural cycle versus IUI in stimulated cycle, Outcome 2 Multiple pregnancy rate per couple.

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Analysis 3.3

Comparison 3 IUI in natural cycle versus IUI in stimulated cycle, Outcome 3 Pregnancy rate per couple (all cycles).

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Analysis 3.4

Comparison 3 IUI in natural cycle versus IUI in stimulated cycle, Outcome 4 Moderate or severe ovarian hyperstimulation syndrome per woman.

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Analysis 3.5

Comparison 3 IUI in natural cycle versus IUI in stimulated cycle, Outcome 5 Miscarriage rate per couple.

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Analysis 3.6

Comparison 3 IUI in natural cycle versus IUI in stimulated cycle, Outcome 6 Ectopic pregnancy rate per couple.

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Analysis 4.1

Comparison 4 IUI in stimulated cycle versus TI or expectant management in natural cycle, Outcome 1 Live birth rate per couple (all cycles).

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Analysis 4.2

Comparison 4 IUI in stimulated cycle versus TI or expectant management in natural cycle, Outcome 2 Multiple pregnancy rate per couple.

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Analysis 4.3

Comparison 4 IUI in stimulated cycle versus TI or expectant management in natural cycle, Outcome 3 Pregnancy rate per couple (all cycles).

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Analysis 4.4

Comparison 4 IUI in stimulated cycle versus TI or expectant management in natural cycle, Outcome 4 Moderate or severe ovarian hyperstimulation syndrome per woman.

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Analysis 4.5

Comparison 4 IUI in stimulated cycle versus TI or expectant management in natural cycle, Outcome 5 Miscarriage rate per couple.

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Analysis 5.1

Comparison 5 IUI in natural cycle versus TI or expectant management in stimulated cycle, Outcome 1 Live birth rate per couple (all cycles).

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Analysis 5.2

Comparison 5 IUI in natural cycle versus TI or expectant management in stimulated cycle, Outcome 2 Multiple pregnancy rate per couple.

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Analysis 5.3

Comparison 5 IUI in natural cycle versus TI or expectant management in stimulated cycle, Outcome 3 Pregnancy rate per couple (all cycles).

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Analysis 5.4

Comparison 5 IUI in natural cycle versus TI or expectant management in stimulated cycle, Outcome 4 Miscarriage rate per couple.

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Analysis 5.5

Comparison 5 IUI in natural cycle versus TI or expectant management in stimulated cycle, Outcome 5 Ectopic pregnancy rate per couple.

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Summary of findings for the main comparison. IUI compared to TI or expectant management both in natural cycle for unexplained subfertility

IUI compared to TI or expectant management both in natural cycle for unexplained subfertility
Patient or population: people with unexplained subfertility Settings: Intervention: IUI Comparison: TI or expectant management both in natural cycle
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	TI or expectant management both in natural cycle	IUI
Live birth rate per couple (all cycles)	156 per 1000	228 per 1000 (145 to 339)	OR 1.60 (0.92 to 2.78)	334 (1 study)	⊕⊕⊕⊝ moderate^1,2
Multiple pregnancy rate per couple	12 per 1000	6 per 1000 (0 to 63)	OR 0.50 (0.04 to 5.53)	334 (1 study)	⊕⊕⊕⊝ moderate^1,2
Pregnancy rate per couple (all cycles)	162 per 1000	228 per 1000 (145 to 338)	OR 1.53 (0.88 to 2.64)	334 (1 study)	⊕⊕⊕⊝ moderate^1,2
Ovarian Hyperstimulation Syndrome rate per woman ‐ not reported			Not estimable	‐
Miscarriage rate per couple	54 per 1000	42 per 1000 (16 to 107)	OR 0.77 (0.28 to 2.11)	334 (1 study)	⊕⊕⊕⊝ moderate^1,2
Ectopic pregnancy rate per couple	Not estimable		OR 5.06 (0.24 to 106.2)	334 (1 study)	⊕⊕⊕⊝ moderate^1,2
The basis for the assumed risk* is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Small sample size ² Effect estimate with wide confidence interval

Summary of findings for the main comparison. IUI compared to TI or expectant management both in natural cycle for unexplained subfertility

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Summary of findings 2. IUI compared to TI or expectant management both in stimulated cycle for unexplained subfertility

IUI compared to TI or expectant management both in stimulated cycle for unexplained subfertility
Patient or population: people with unexplained subfertility Settings: Intervention: IUI Comparison: TI both in stimulated cycle
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	TI both in stimulated cycle	IUI
Live birth rate per couple (all cycles)	255 per 1000	352 per 1000 (231 to 496)	OR 1.59 (0.88 to 2.88)	208 (2 studies)	⊕⊕⊕⊝ moderate^1,2
Multiple pregnancy rate per couple	43 per 1000	62 per 1000 (24 to 148)	OR 1.46 (0.55 to 3.87)	316 (4 studies)	⊕⊕⊝⊝ low^2,3
Pregnancy rate per couple (all cycles)	234 per 1000	339 per 1000 (257 to 433)	OR 1.69 (1.14 to 2.53)	517 (7 studies)	⊕⊕⊝⊝ low^1,2,3
Ovarian Hyperstimulation Syndrome rate per woman	not estimable		OR 2.75 (0.11 to 69.83)	68 (1 study)	⊕⊕⊝⊝ low^2,3,4
Miscarriage rate per couple	57 per 1000	91 per 1000 (33 to 228)	OR 1.66 (0.56 to 4.88)	208 (2 studies)	⊕⊕⊕⊝ moderate^1,2
Ectopic pregnancy rate per couple	not estimable		OR 3.06 (0.12 to 76.95)	100 (1 study)	⊕⊕⊕⊝ moderate^1,2
The basis for the assumed risk* is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Small sample size ² Effect estimate with wide confidence interval ³ Most domains of risk of bias were assessed as either 'unclear' or 'high risk' ⁴ Only one event in one study was reported

Summary of findings 2. IUI compared to TI or expectant management both in stimulated cycle for unexplained subfertility

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Summary of findings 3. IUI in natural cycle compared to IUI in stimulated cycle for unexplained subfertility

IUI in natural cycle compared to IUI in stimulated cycle for unexplained subfertility
Patient or population: people with unexplained subfertility Settings: Intervention: IUI in natural cycle Comparison: IUI in stimulated cycle
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	IUI in stimulated cycle	IUI in natural cycle
Live birth rate per couple (all cycles)	248 per 1000	137 per 1000 (87 to 213)	OR 0.48 (0.29 to 0.82)	396 (4 studies)	⊕⊕⊕⊝ moderate^1,2
Multiple pregnancy rate per couple	33 per 1000	11 per 1000 (0 to 229)	OR 0.33 (0.01 to 8.7)	65 (2 studies)	⊕⊕⊝⊝ low^1,2
Pregnancy rate per couple (all cycles)	300 per 1000	64 per 1000 (4 to 431)	OR 0.16 (0.01 to 1.77)	26 (1 study)	⊕⊕⊕⊝ moderate^1,2
Ovarian Hyperstimulation Syndrome rate per woman⁵ ‐ not measured			Not estimable³	‐
Miscarriage rate per couple	100 per 1000	21 per 1000 (1 to 366)	OR 0.19 (0.01 to 5.2)	26 (1 study)	⊕⊕⊝⊝ low^1,2
Ectopic pregnancy rate per couple	23 per 1000	4 per 1000 (0 to 66)	OR 0.15 (0.01 to 3.02)	250 (2 studies)	⊕⊕⊕⊝ moderate^1,2
The basis for the assumed risk* is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Small sample size ² Effect estimate with wide confidence interval ³ No usable data were reported

Summary of findings 3. IUI in natural cycle compared to IUI in stimulated cycle for unexplained subfertility

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Summary of findings 4. IUI in stimulated cycle compared to TI or expectant management in natural cycle for unexplained subfertility

IUI in stimulated cycle compared to TI or expectant management in natural cycle for unexplained subfertility
Patient or population: people with unexplained subfertility Settings: Intervention: IUI in stimulated cycle Comparison: TI or expectant management in natural cycle
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	TI or expectant management in natural cycle	IUI in stimulated cycle
Live birth rate per couple (all cycles)	238 per 1000	204 per 1000 (123 to 318)	OR 0.82 (0.45 to 1.49)	253 (1 study)	⊕⊕⊕⊝ moderate^1,2
Multiple pregnancy rate per couple	6 per 1000	13 per 1000 (1 to 128)	OR 2.00 (0.18 to 22.34)	304 (2 studies)	⊕⊕⊕⊝ moderate^1,2
Pregnancy rate per couple (all cycles)	247 per 1000	247 per 1000 (162 to 354)	OR 1.00 (0.59 to 1.67)	304 (2 studies)	⊕⊕⊕⊝ moderate^1,2
Ovarian Hyperstimulation rate per woman ‐ not measured			Not estimable	‐
Miscarriage rate per couple	48 per 1000	103 per 1000 (41 to 238)	OR 2.28 (0.84 to 6.2)	253 (1 study)	⊕⊕⊕⊝ moderate^1,2
Ectopic pregnancy rate per couple ‐ not reported	See comment	See comment	Not estimable	‐	See comment
The basis for the assumed risk* is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Small sample size ² Effect estimate with wide confidence interval

Summary of findings 4. IUI in stimulated cycle compared to TI or expectant management in natural cycle for unexplained subfertility

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Summary of findings 5. IUI in natural cycle compared to TI or expectant management in stimulated cycle for unexplained subfertility

IUI in natural cycle compared to TI or expectant management in stimulated cycle for unexplained subfertility
Patient or population: people with unexplained subfertility Settings: Intervention: IUI in natural cycle Comparison: TI in stimulated cycle
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	TI in stimulated cycle	IUI in natural cycle
Live birth rate per couple (all cycles)	131 per 1000	227 per 1000 (142 to 341)	OR 1.95 (1.1 to 3.44)	342 (1 study)	⊕⊕⊕⊝ moderate¹
Multiple pregnancy rate per couple	6 per 1000	6 per 1000 (0 to 88)	OR 1.05 (0.07 to 16.9)	342 (1 study)	⊕⊕⊕⊝ moderate^1,2
Pregnancy rate per couple (all cycles)	143 per 1000	228 per 1000 (144 to 339)	OR 1.77 (1.01 to 3.08)	342 (1 study)	⊕⊕⊕⊝ moderate¹
Ovarian Hyperstimulation Syndrome rate per woman ‐ not reported			Not estimable	‐
Miscarriage rate per couple	46 per 1000	42 per 1000 (15 to 111)	OR 0.91 (0.32 to 2.58)	342 (1 study)	⊕⊕⊕⊝ moderate^1,2
Ectopic pregnancy rate per couple	Not estimable		OR 5.30 (0.25 to 111.3)	342 (1 study)	⊕⊕⊕⊝ moderate^1,2
The basis for the assumed risk* is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Small sample size ² Effect estimate with wide confidence interval

Summary of findings 5. IUI in natural cycle compared to TI or expectant management in stimulated cycle for unexplained subfertility

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Comparison 1. IUI versus TI or expectant management both in natural cycle

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth rate per couple (all cycles) Show forest plot	1	334	Odds Ratio (M‐H, Fixed, 95% CI)	1.60 [0.92, 2.78]

2 Multiple pregnancy rate per couple Show forest plot	1	334	Odds Ratio (M‐H, Fixed, 95% CI)	0.50 [0.04, 5.53]

3 Pregnancy rate per couple (all cycles) Show forest plot	1	334	Odds Ratio (M‐H, Fixed, 95% CI)	1.53 [0.88, 2.64]

4 Miscarriage rate per couple Show forest plot	1	334	Odds Ratio (M‐H, Fixed, 95% CI)	0.77 [0.28, 2.11]

5 Ectopic pregnancy rate per couple Show forest plot	1	334	Odds Ratio (M‐H, Fixed, 95% CI)	5.06 [0.24, 106.21]

Comparison 1. IUI versus TI or expectant management both in natural cycle

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Comparison 2. IUI versus TI or expectant management both in stimulated cycle

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth rate per couple (all cycles) Show forest plot	2	208	Odds Ratio (M‐H, Fixed, 95% CI)	1.59 [0.88, 2.88]

1.1 Gonadotropins	2	208	Odds Ratio (M‐H, Fixed, 95% CI)	1.59 [0.88, 2.88]
2 Multiple pregnancy rate per couple Show forest plot	4	316	Odds Ratio (M‐H, Fixed, 95% CI)	1.46 [0.55, 3.87]

2.1 Clomiphene Citrate	1	40	Odds Ratio (M‐H, Fixed, 95% CI)	0.43 [0.02, 11.18]
2.2 Gonadotropins	2	208	Odds Ratio (M‐H, Fixed, 95% CI)	1.61 [0.44, 5.89]
2.3 Clomiphene Citrate and Gonadotropins	1	68	Odds Ratio (M‐H, Fixed, 95% CI)	1.88 [0.32, 11.00]
3 Pregnancy rate per couple (all cycles) Show forest plot	6	517	Odds Ratio (M‐H, Fixed, 95% CI)	1.69 [1.14, 2.53]

3.1 Clomiphene Citrate	1	40	Odds Ratio (M‐H, Fixed, 95% CI)	0.30 [0.03, 2.93]
3.2 Gonadotropins	4	319	Odds Ratio (M‐H, Fixed, 95% CI)	1.68 [1.03, 2.75]
3.3 Clomiphene Citrate and Gonadotropins	1	68	Odds Ratio (M‐H, Fixed, 95% CI)	2.62 [0.98, 6.98]
3.4 Clomiphene citrate OR Gonadotropins	1	90	Odds Ratio (M‐H, Fixed, 95% CI)	1.72 [0.50, 5.89]
4 Moderate or severe ovarian hyperstimulation syndrome rate per woman Show forest plot	2		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Gonadotropins	1	108	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Clomiphene Citrate and Gonadotropins	1	68	Odds Ratio (M‐H, Fixed, 95% CI)	2.75 [0.11, 69.83]
5 Miscarriage rate per couple Show forest plot	2	208	Odds Ratio (M‐H, Fixed, 95% CI)	1.66 [0.56, 4.88]

5.1 Gonadotropins	2	208	Odds Ratio (M‐H, Fixed, 95% CI)	1.66 [0.56, 4.88]
6 Ectopic pregnancy rate per couple Show forest plot	1	100	Odds Ratio (M‐H, Fixed, 95% CI)	3.06 [0.12, 76.95]

6.1 Gonadotropins	1	100	Odds Ratio (M‐H, Fixed, 95% CI)	3.06 [0.12, 76.95]

Comparison 2. IUI versus TI or expectant management both in stimulated cycle

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Comparison 3. IUI in natural cycle versus IUI in stimulated cycle

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth rate per couple (all cycles) Show forest plot	4	396	Odds Ratio (M‐H, Fixed, 95% CI)	0.48 [0.29, 0.82]

1.1 Clomiphene Citrate	1	26	Odds Ratio (M‐H, Fixed, 95% CI)	0.27 [0.02, 3.41]
1.2 Gonadotropins	3	370	Odds Ratio (M‐H, Fixed, 95% CI)	0.50 [0.29, 0.85]
2 Multiple pregnancy rate per couple Show forest plot	2	65	Odds Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 8.70]

2.1 Clomiphene Citrate	1	26	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 Gonadotropins	1	39	Odds Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 8.70]
3 Pregnancy rate per couple (all cycles) Show forest plot	1	26	Odds Ratio (M‐H, Fixed, 95% CI)	0.16 [0.01, 1.77]

3.1 Clomiphene Citrate	1	26	Odds Ratio (M‐H, Fixed, 95% CI)	0.16 [0.01, 1.77]
4 Moderate or severe ovarian hyperstimulation syndrome per woman Show forest plot	3	185	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

4.1 Clomiphene Citrate	1	26	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Gonadotropins	2	159	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Miscarriage rate per couple Show forest plot	1	26	Odds Ratio (M‐H, Fixed, 95% CI)	0.19 [0.01, 5.20]

5.1 Clomiphene Citrate	1	26	Odds Ratio (M‐H, Fixed, 95% CI)	0.19 [0.01, 5.20]
5.2 Gonadotropins	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Ectopic pregnancy rate per couple Show forest plot	2	250	Odds Ratio (M‐H, Fixed, 95% CI)	0.15 [0.01, 3.02]

6.1 Gonadotropins	2	250	Odds Ratio (M‐H, Fixed, 95% CI)	0.15 [0.01, 3.02]

Comparison 3. IUI in natural cycle versus IUI in stimulated cycle

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Comparison 4. IUI in stimulated cycle versus TI or expectant management in natural cycle

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth rate per couple (all cycles) Show forest plot	1	253	Odds Ratio (M‐H, Fixed, 95% CI)	0.82 [0.45, 1.49]

2 Multiple pregnancy rate per couple Show forest plot	2	304	Odds Ratio (M‐H, Fixed, 95% CI)	2.0 [0.18, 22.34]

2.1 Clomiphene Citrate	1	51	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 Clomiphene Citrate or Gonadotropins	1	253	Odds Ratio (M‐H, Fixed, 95% CI)	2.0 [0.18, 22.34]
3 Pregnancy rate per couple (all cycles) Show forest plot	2	304	Odds Ratio (M‐H, Fixed, 95% CI)	1.00 [0.59, 1.67]

3.1 Clomiphene Citrate	1	51	Odds Ratio (M‐H, Fixed, 95% CI)	3.2 [0.82, 12.50]
3.2 Clomiphene Citrate or Gonadotropins	1	253	Odds Ratio (M‐H, Fixed, 95% CI)	0.80 [0.45, 1.42]
4 Moderate or severe ovarian hyperstimulation syndrome per woman Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

4.1 Clomiphene Citrate	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Clomiphene Citrate or Gonadotropins	0		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Miscarriage rate per couple Show forest plot	1	253	Odds Ratio (M‐H, Fixed, 95% CI)	2.28 [0.84, 6.20]

Comparison 4. IUI in stimulated cycle versus TI or expectant management in natural cycle

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Comparison 5. IUI in natural cycle versus TI or expectant management in stimulated cycle

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth rate per couple (all cycles) Show forest plot	1	342	Odds Ratio (M‐H, Fixed, 95% CI)	1.95 [1.10, 3.44]

2 Multiple pregnancy rate per couple Show forest plot	1	342	Odds Ratio (M‐H, Fixed, 95% CI)	1.05 [0.07, 16.90]

3 Pregnancy rate per couple (all cycles) Show forest plot	1	342	Odds Ratio (M‐H, Fixed, 95% CI)	1.77 [1.01, 3.08]

4 Miscarriage rate per couple Show forest plot	1	342	Odds Ratio (M‐H, Fixed, 95% CI)	0.91 [0.32, 2.58]

5 Ectopic pregnancy rate per couple Show forest plot	1	342	Odds Ratio (M‐H, Random, 95% CI)	5.30 [0.25, 111.26]

Comparison 5. IUI in natural cycle versus TI or expectant management in stimulated cycle

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Intra‐uterine insemination for unexplained subfertility

Appendices

Appendix 1. MDSG search strategy

Appendix 2. CENTRAL search strategy

Appendix 3. MEDLINE search strategy

Appendix 4. EMBASE search strategy

Appendix 5. PsycINFO search strategy

Appendix 6. Prognostic factors in included studies

Appendix 7. Sensitivity analyses: intra‐uterine insemination (IUI) versus timed intercourse (TI) both in a stimulated cycle

Appendix 8. Sensitivity analyses: IUI in a natural cycle versus IUI in a stimulated cycle

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Appendices

Appendix 1. MDSG search strategy

Appendix 2. CENTRAL search strategy

Appendix 3. MEDLINE search strategy

Appendix 4. EMBASE search strategy

Appendix 5. PsycINFO search strategy

Appendix 6. Prognostic factors in included studies

Appendix 7. Sensitivity analyses: intra‐uterine insemination (IUI) versus timed intercourse (TI) both in a stimulated cycle

Appendix 8. Sensitivity analyses: IUI in a natural cycle versus IUI in a stimulated cycle

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